RESUMO
Throughout the golden age of antibiotic discovery, Streptomyces have been unsurpassed for their ability to produce bioactive metabolites. Yet, this success has been hampered by rediscovery. As we enter a new stage of biodiscovery, omics data and existing scientific repositories can enable informed choices on the biodiversity that may yield novel antibiotics. Here, we focus on the chemical potential of rare actinomycetes, defined as bacteria within the order Actinomycetales, but not belonging to the genus Streptomyces. They are named as such due to their less-frequent isolation under standard laboratory practices, yet there is increasing evidence to suggest these biologically diverse genera harbour considerable biosynthetic and chemical diversity. In this review, we focus on examples of successful isolation and genera that have been the focus of more concentrated biodiscovery efforts, we survey the representation of rare actinomycete taxa, compared with Streptomyces, across natural product data repositories in addition to its biosynthetic potential. This is followed by an overview of clinically useful drugs produced by rare actinomycetes and considerations for future biodiscovery efforts. There is much to learn about these underexplored taxa, and mounting evidence suggests that they are a fruitful avenue for the discovery of novel antimicrobials.
Assuntos
Actinobacteria , Streptomyces , Actinobacteria/genética , Actinobacteria/metabolismo , Actinomyces , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Streptomyces/genética , BiodiversidadeRESUMO
Streptomyces bacteria make numerous secondary metabolites, including half of all known antibiotics. Production of antibiotics is usually coordinated with the onset of sporulation but the cross regulation of these processes is not fully understood. This is important because most Streptomyces antibiotics are produced at low levels or not at all under laboratory conditions and this makes large scale production of these compounds very challenging. Here, we characterize the highly conserved actinobacterial two-component system MtrAB in the model organism Streptomyces venezuelae and provide evidence that it coordinates production of the antibiotic chloramphenicol with sporulation. MtrAB are known to coordinate DNA replication and cell division in Mycobacterium tuberculosis where TB-MtrA is essential for viability but MtrB is dispensable. We deleted mtrB in S. venezuelae and this resulted in a global shift in the metabolome, including constitutive, higher-level production of chloramphenicol. We found that chloramphenicol is detectable in the wild-type strain, but only at very low levels and only after it has sporulated. ChIP-seq showed that MtrA binds upstream of DNA replication and cell division genes and genes required for chloramphenicol production. dnaA, dnaN, oriC, and wblE (whiB1) are DNA binding targets for MtrA in both M. tuberculosis and S. venezuelae. Intriguingly, over-expression of TB-MtrA and gain of function TB- and Sv-MtrA proteins in S. venezuelae also switched on higher-level production of chloramphenicol. Given the conservation of MtrAB, these constructs might be useful tools for manipulating antibiotic production in other filamentous actinomycetes.
RESUMO
Members of the Rrf2 superfamily of transcription factors are widespread in bacteria but their functions are largely unexplored. The few that have been characterized in detail sense nitric oxide (NsrR), iron limitation (RirA), cysteine availability (CymR) and the iron sulfur (Fe-S) cluster status of the cell (IscR). In this study we combined ChIP- and dRNA-seq with in vitro biochemistry to characterize a putative NsrR homologue in Streptomyces venezuelae. ChIP-seq analysis revealed that rather than regulating the nitrosative stress response like Streptomyces coelicolor NsrR, Sven6563 binds to a conserved motif at a different, much larger set of genes with a diverse range of functions, including a number of regulators, genes required for glutamine synthesis, NADH/NAD(P)H metabolism, as well as general DNA/RNA and amino acid/protein turn over. Our biochemical experiments further show that Sven6563 has a [2Fe-2S] cluster and that the switch between oxidized and reduced cluster controls its DNA binding activity in vitro. To our knowledge, both the sensing domain and the putative target genes are novel for an Rrf2 protein, suggesting Sven6563 represents a new member of the Rrf2 superfamily. Given the redox sensitivity of its Fe-S cluster we have tentatively named the protein RsrR for Redox sensitive response Regulator.
Assuntos
Proteínas de Bactérias , Proteínas Ferro-Enxofre , Streptomyces , Fatores de Transcrição , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/metabolismo , Motivos de Nucleotídeos , Ligação Proteica , Homologia de Sequência de Aminoácidos , Streptomyces/genética , Streptomyces/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Insect fungiculture is practiced by ants, termites, beetles, and gall midges and it has been suggested to be widespread among plant-ants. Some of the insects engaged in fungiculture, including attine ants and bark beetles, are known to use symbiotic antibiotic-producing actinobacteria to protect themselves and their fungal cultivars against infection. In this study, we analyze the bacterial communities on the cuticles of the plant-ant genera Allomerus and Tetraponera using deep sequencing of 16S rRNA. Allomerus ants cultivate fungus as a building material to strengthen traps for prey, while Tetraponera ants cultivate fungus as a food source. We report that Allomerus and Tetraponera microbiomes contain >75% Proteobacteria and remarkably the bacterial phyla that dominate their cuticular microbiomes are very similar despite their geographic separation (South America and Africa, respectively). Notably, antibiotic-producing actinomycete bacteria represent a tiny fraction of the cuticular microbiomes of both Allomerus and Tetraponera spp. and instead they are dominated by γ-proteobacteria Erwinia and Serratia spp. Both these phyla are known to contain antibiotic-producing species which might therefore play a protective role in these ant-plant systems.